Sulopenem hits key end point in phase 3 uncomplicated UTI trial

Sulopenem demonstrated superior clinical activity over ciprofloxacin in patients with uncomplicated urinary tract infections (uUTI) with quinolone resistant pathogens, meeting a coprimary end point of the phase 3 SURE1 trial, according to Iterum Therapeutics plc, the manufacturer of the novel oral penem anti-infective compound.

In the quinolone non-susceptible microbiologic-modified intent-to-treat (micro-MITT) population, the overall response rate (ORR) at the test of cure (TOC) visit was 62.6% (92 of 147 patients) in the sulopenem arm compared with 36% (50 of 139 patients) in the ciprofloxacin arm, for a statically significant percentage difference of 26.6% (95% CI, 15.1-37.4; P <.001). The TOC visit clinical response was 83% (n = 122) versus 62.6% (n = 87), respectively (P <.001), and the end of treatment (EOT) visit ORR was 64.6% (n = 95) versus 30.2% (n = 42), respectively (P <.001).

The same benefit was not observed in the quinolone-susceptible micro-MITT population in SURE1, missing the other coprimary end point of the trial. In this subgroup, sulopenem failed to demonstrate noninferiority versus ciprofloxacin.

“Superiority trials to define the effectiveness of novel antibacterial agents are rarely performed but remain the ultimate test for defining the value of a new agent in an area of high unmet medical need. Sulopenem has demonstrated efficacy in the treatment of UTI due to a quinolone resistant organism, a scenario found in almost 30% of all urinary tract infections in women in the United States today,” Michael Dunne, MD, chief scientific officer of Iterum Therapeutics, stated in a press release.

The multicenter, double-blind phase 3 SURE1 trial included 1670 women with uUTI. Patients were randomized to oral sulopenem/probenecid twice daily for 5 days, or oral ciprofloxacin twice daily for 3 days. The EOT and TOC visits occurred on days 5 and 12, respectively. The independent coprimary end points were ORR at the TOC visit in the quinolone-resistant and -susceptible populations. The resistant group was tested for superiority, which the study design defined as a P value <.05. The susceptible group was tested for noninferiority, defined as a lower limit of the 95% confidence interval being above -10% in the micro-MITT population.

The ORR at the TOC visit in the quinolone-susceptible population was 66.8% with sulopenem versus 78.6% with ciprofloxacin, a percentage difference of -11.8%, with a 95% confidence interval of -18.0% to -5.6%, thus missing the comprimary end point. The researchers attributed this difference in outcomes to the fact that 12.7% of patients receiving sulopenem had asymptomatic bacteriuria, compared with 3.9% of patients receiving ciprofloxacin.

“The difference in the overall response to treatment in the population of patients with a quinolone-susceptible baseline pathogen was driven to a large degree by a greater amount of asymptomatic bacteriuria in the sulopenem treated patients relative to those receiving ciprofloxacin,” stated Dunne.

“This same finding was observed in the recently completed phase 3 clinical trial of sulopenem in complicated urinary tract infections, SURE2. In that study, the difference in outcome between ertapenem and sulopenem was driven largely by the post therapy rate of asymptomatic bacteriuria and, notably, was lower only in those patients who received ertapenem followed by ciprofloxacin and not in any other pairwise comparison with sulopenem or ertapenem treated patients. The clinical significance of post treatment asymptomatic bacteriuria and its relationship to oral dosing with ciprofloxacin will be the focus of additional investigation,” added Dunne.

The safety population included 1660 patients. Treatment-related adverse events (AEs) across all grades occurred in 11.4% of the sulopenem arm compared with 11.9% of the ciprofloxacin arm. The most frequently occurring AEs were diarrhea (7.3% in the sulopenem arm vs 7.6% in the ciprofloxacin arm), nausea (3.4% vs 4%, respectively), and headache (2.2% in both arms). There were no treatment-related serious AEs in the sulopenem cohort compared with 1 in the ciprofloxacin cohort. AE-related discontinuations occurred in 1.1% and 1.5% of the sulopenem and ciprofloxacin arms, respectively.

“We are extremely pleased to have a potential path to approval for sulopenem in uUTI.Approximately 5 to 6 million urinary tract infections in the United States every year are caused by quinolone-resistant pathogens. If approved, sulopenem would provide a treatment option for women with infections due to these resistant pathogens,” Corey Fishman, chief executive officer of Iterum Therapeutics, stated in the press release.

“Sulopenem is the first new oral antibiotic to demonstrate success in treating uUTIs in a phase 3 trial in over 20 years,” added Fishman. “We anticipate a pre-NDA meeting with the FDA in the third quarter of 2020 to discuss a path forward.”

Reference

Iterum Therapeutics Announces Topline Results from its Phase 3 Clinical Trial of Oral Sulopenem for the Treatment of Uncomplicated Urinary Tract Infections. Published June 29, 2020. https://bit.ly/2BL6e3n. Access June 29, 2020.